SYMFI (Page 3 of 16)

Mineralization Defects

Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with TDF use [see Adverse Reactions (6.2)]. Arthralgia and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving TDF-containing products [see Warnings and Precautions (5.4)].

5.14 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including EFV, 3TC, and TDF. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barre syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.15 Fat Redistribution

In HIV-infected patients, redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving combination antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

5.16 QTc Prolongation

QTc prolongation has been observed with the use of EFV [see Drug Interactions (7.2, 7.5) and Clinical Pharmacology (12.2)]. Consider alternatives to products containing EFV when coadministered with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsade de Pointes.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in other sections of the labeling:

Exacerbations of Hepatitis B [see Boxed Warning, Warnings and Precautions (5.1)].
Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.2)].
New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.4)].
Psychiatric Symptoms [see Warnings and Precautions (5.5)].
Nervous System Symptoms [see Warnings and Precautions (5.6)].
Skin and Systemic Hypersensitivity Reaction [see Warnings and Precautions (5.8)].
Hepatotoxicity [see Warnings and Precautions (5.9)].
Pancreatitis [see Warnings and Precautions (5.10)].
Bone Loss and Mineralization Effects [see Warnings and Precautions (5.13)].
Immune Reconstitution Syndrome [see Warnings and Precautions (5.14)].
Fat Redistribution [see Warnings and Precautions (5.15)].

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, the adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate

Clinical Trials in Treatment-Naïve HIV-1 Infected Adult Subjects

In Trial 903, 600 antiretroviral-naïve subjects received TDF (N = 299) or stavudine (d4T) (N = 301) administered in combination with 3TC and EFV for 144 weeks. The most common adverse reactions were mild to moderate gastrointestinal events and dizziness. Mild adverse reactions (Grade 1) were common with a similar incidence in both arms and included dizziness, diarrhea, and nausea. Table 1 provides the treatment-emergent adverse reactions (Grades 2-4) occurring in greater than or equal to 5% of subjects treated in any treatment group.

Table 1. Selected Adverse Reactions * (Grades 2-4) Reported in ≥ 5% in Any Treatment Group in Trial 903 (0-144 Weeks)
*
Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.
Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.
Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome.
§
Peripheral neuropathy includes peripheral neuritis and neuropathy.

TDF + 3TC + EFV

d4T + 3TC + EFV

N = 299

N = 301

Rash event

18%

12%

Headache

14%

17%

Pain

13%

12%

Diarrhea

11%

13%

Depression

11%

10%

Back pain

9%

8%

Nausea

8%

9%

Fever

8%

7%

Abdominal pain

7%

12%

Asthenia

6%

7%

Anxiety

6%

6%

Vomiting

5%

9%

Insomnia

5%

8%

Arthralgia

5%

7%

Pneumonia

5%

5%

Dyspepsia

4%

5%

Dizziness

3%

6%

Myalgia

3%

5%

Lipodystrophy

1%

8%

Peripheral neuropathy §

1%

5%

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